Project Summary/Abstract The mammalian renal pelvis is a pouch-like structure into which urine flows from the terminal portions of the collecting ducts. There is increasing evidence that the uroepithelial cells lining the renal pelvis do not simply perform a barrier function in protecting the underlying tissue from large changes in urinary pH and ion concentration but may play an important role in whole body sodium and water balance, and blood pressure control. In this regard, previous studies have demonstrated that the renal pelvic uroepithelium mediates a renorenal reflex response wherein changes in renal pelvic hydrostatic pressure modulate renal sodium and water excretion and systemic blood pressure. Recently we have demonstrated that the electrogenic sodium bicarbonate cotransporter, NBC4c, first cloned in our laboratory and encoded by the SLC4A5 gene is specifically expressed in the mammalian kidney on the apical membrane of uroepithelial cells lining the renal pelvis. Recent linkage analysis studies in humans have implicated SLC4A5 as a candidate hypertension- susceptibility gene, suggesting an important and as yet uncharacterized role for NBC4c in blood pressure control. We hypothesized that NBC4c plays a key role in the reflex modulation of renal sodium and water excretion in response to changes in renal pelvic hydrostatic pressure. In preliminary experiments, an increase in hydrostatic pressure stimulated the flux through NBC4c in renal pelvic uroepithelial cells. In this first part of this proposal, we will characterize the signaling pathway(s) involved in the stimulation of NBC4c-mediated transport in uroepithelial cells. In the second part of this proposal, we will study the pathways involved in switching off the signaling cascade. In particular, the specific role of the calcium-dependent phosphatase calcineurin will be studied. This proposal will enhance our understanding of the biology of sodium bicarbonate cotransport in the renal pelvis and its important physiological role in sodium and water homeostasis in the kidney and whole organism. Public Health Relevance Statement High blood pressure (hypertension) is an important cause of heart, brain and kidney disease in the United States. Recent studies have implicated NBC4 as a new candidate protein that is associated with high blood pressure however the mechanism is entirely unknown. The results of the studies in this proposal will lead to an increased understanding of the role that NBC4 plays in blood pressure control and potentially lead to important new approaches for treating high blood pressure.